Methamphetamine addiction is growing national public health problem, yet to date there are no approved pharmacological treatments for this disorder. In recent years, animal studies have demonstrated that the type 5 metabotropic glutamate receptor (mGluR5) is involved in various aspects of experimental addiction. For example, mice lacking mGluR5 receptors do not self-administer cocaine and are indifferent to its locomotor stimulant effects. Similarly, selective mGluR5 antagonists (also known as negative allosteric modulators) reduce the reinforcing effects of cocaine, heroin, nicotine, and alcohol in rodents and/or non-human primates. Selective mGluR5 antagonists also reduce relapse-like behavior in these species, are currently being tested in Phase I and II clinical trials for the treatment of other medical conditions including depression, anxiety, migraine, gastroesophageal reflux disease, and Fragile X Syndrome. Thus far, these compounds appear to be well tolerated by human subjects with no serious adverse side effects. We have generated encouraging preliminary data in rats that the selective mGluR5 antagonist 3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine (MTEP) dose-dependently reduces intravenous methamphetamine self-administration, breakpoints for methamphetamine on a progressive ratio schedule of reinforcement, as well as reinstatement of methamphetamine-seeking behavior elicited by drug-associated cues and drug priming. These effects of MTEP are not likely due to a generalized inhibition of behavioral output, since we have observed that MTEP does not alter food self-administration, breakpoints for food on a progressive ratio schedule of reinforcement, or cue-induced reinstatement of food-seeking behavior. These data support our overall hypothesis that mGluR5 antagonists may be novel pharmacological agents for use in the treatment of methamphetamine addiction. In the present application, we propose additional preclinical medications development studies to further explore the potential utility of mGluR5 antagonists in the treatment of addiction to methamphetamine. Specifically, we propose to examine the effects of MTEP and the clinically validated mGluR5 antagonist fenobam in rodent models of methamphetamine addiction that more closely resemble patterns of human methamphetamine use (prolonged daily self-administration and binge-abstinent patterns of intake). In Specific Aim 1, we will test the hypothesis that selective mGluR5 antagonists will reduce the reinforcing effects of methamphetamine following escalation of intake produced by extended drug access. In Specific Aim 2, we will test the hypothesis that selective mGluR5 antagonists will attenuate the increases in the reinforcing efficacy of methamphetamine observed following binge-abstinent patterns of self-administration. Together, these medications development studies will provide a preclinical basis for the use of mGluR5 antagonists in the treatment of methamphetamine addiction in humans. PUBLIC HEALTH RELEVANCE: The goal of this proposal is to provide a preclinical basis for the potential use of mGluR5 antagonists for the treatment of methamphetamine addiction. Should such compounds eventually prove to be effective in the treatment of methamphetamine addiction in humans, this would represent a major public health advancement and would significantly reduce the medical, socioeconomic and legal costs of this disorder to society.